Project Summary/Abstract This project seeks to enhance our understanding of the clinical features, long-term consequences, and genetic underpinnings of delayed puberty, a common condition that affects 2-3% of adolescents. While delayed puberty has been reported to have negative effects on final height, bone mineral density, and self- esteem in adulthood, it remains unclear which patients with delayed puberty are at greatest risk for these outcomes. Furthermore, we have limited understanding of the physiological and genetic mechanisms that underlie delayed puberty. This project treats delayed puberty not as a single, monolithic entity, but as a clinical phenotype that can be produced by at least two mechanisms. One mechanism is a global slowing of the developmental program that regulates not just the timing of puberty but also the pace of childhood growth and skeletal maturation; this global slowing is often called constitutional delay of growth and puberty (CDGP). The other mechanism is a delay in pubertal timing in the absence of other delays in growth or skeletal maturation, producing an isolated delay in pubertal timing. These mechanisms are not mutually exclusive, and both could potentially contribute to delayed puberty in an individual. The first Aim of this project explores the clinical heterogeneity in delayed puberty by reviewing clinical records of delayed puberty patients and identifying correlations between variables using univariate and multivariate analyses. Aim 1 will also use latent class analysis, an unbiased, data-driven method, to identify distinct subgroups within delayed puberty. The second Aim of this project assesses adults with a history of delayed puberty to determine if these adults have impairments in height, bone mineral density, self-esteem, or sperm counts (in men) compared to healthy control adults who had normal pubertal timing. The Aim further assesses whether these outcomes differ across predictor variables such as sex, body mass index, and prior treatment with sex steroids and/or across the different subgroups of delayed puberty identified in Aim 1. The third Aim of this project seeks to identify the genetic causes of delayed puberty by examining the contributions of both rare variants (identified through whole-exome sequencing) and common variants (identified through genotyping of single-nucleotide polymorphisms). This Aim will also link these genetic causes to the subgroups of delayed puberty identified in Aim 1 and the adult outcomes examined in Aim 2. By identifying the pathophysiologic mechanisms and genetic causes underlying delayed puberty, as well as the clinical outcomes associated with these factors, these studies will improve our understanding of a common pediatric condition and may lead to new insights into the mysteries of how the pace of childhood growth and the timing of puberty are determined.